The present invention relates to the potentiation of glutamate receptor function using certain sulphonamide derivatives. It also relates to novel sulphonamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropicxe2x80x9d. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, Molecular Pharmacology 44: 505-510, 1993. It is not yet known how these sub-units are combined in the natural state. However, the structures of certain human variants of each sub-unit have been elucidated, and cell lines expressing individual sub-unit variants have been cloned and incorporated into test systems designed to identify compounds which bind to or interact with them, and hence which may modulate their function. Thus, European patent application, publication number EP-A2-0574257 discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B. European patent application, publication number EP-A1-0583917 discloses the human sub-unit variant GluR4B.
One distinctive property of AMPA and kainic acid receptors is their rapid deactivation and desensitization to glutamate. Yamada and Tang, The Journal of Neuroscience, September 1993, 13(9): 3904-3915 and Kathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634-6647. The physiological implications of rapid desensitization, and deactivation if any, are unknown.
It is known that the rapid desensitization and deactivation of AMPA and/or kainic acid receptors to glutamate may be inhibited using certain compounds. This action of these compounds is often referred to in the alternative as xe2x80x9cpotentiationxe2x80x9d of the receptors. One such compound, which selectively potentiates AMPA receptor function, is cyclothiazide. Partin et al., Neuron. Vol. 11, 1069-1082, 1993. Compounds which potentiate AMPA receptors, like cyclothiazide, are often referred to as ampakines.
International Patent Application Publication Number WO 9625926 discloses a group of phenylthioalkylsulphonamides, S-oxides and homologs which are said to potentiate membrane currents induced by kainic acid and AMPA.
Ampakines have been shown to improve memory in a variety of animal tests. Staubli et al., Proc. Natl. Acad. Sci., Vol. 91, pp 777-781, 1994, Neurobiology, and Arai et al., The Journal of Pharmacology and Experimental Therapeutics, 278: 627-638, 1996.
It has now been found that cyclothiazide and certain sulphonamide derivatives potentiate agonist-induced excitability of human GluR4B receptor expressed in HEK 293 cells. Since cyclothiazide is known to potentiate glutamate receptor function in vivo, it is believed that this finding portends that the sulphonamide derivatives will also potentiate glutamate receptor function in vivo, and hence that the compounds will exhibit ampakine-like behavior.
In addition, certain sulfonamide derivatives which potentiate glutamate receptor function in a mammal have been disclosed in International Patent Application Publication WO 98/33496 published Aug. 6, 1998.
Accordingly, the present invention provides a compound of the formula: 
wherein:
one or both of Ra and Rb are selected independently from F, CF3 and xe2x80x94ORc wherein Rc is hydrogen or (1-4C)alkyl, and any remainder is hydrogen; or Ra and Rb together represent xe2x95x90O or xe2x95x90CH2;
R1 represents a naphthyl group or a phenyl, furyl, thienyl or pyridyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen; nitro; cyano; hydroxyimino; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl; (CH2)yX1R9 in which y is 0 or an integer of from 1 to 4, X1 represents O, S, NR10, CO, COO, OCO, CONR11, NR12CO, NR12COCOO or OCONR13, R9 represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10, R11, R12 and R13 each independently represents hydrogen or (1-10C)alkyl, or R9 and R10, R11, R12 or R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl; (1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R14xe2x80x94(La)nxe2x80x94X2xe2x80x94(Lb)m in which X2 represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH or CHxe2x95x90CH, La and Lb each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, nitro, cyano, hydroxyimino, (1-10C) alkyl, (2-10C)alkenyl, (2-10C)alkynyl, (3-8C)-cycloalkyl, 4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and (CH2)zX3R15 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH(OH), COO, OCO, CONR17, NR18CO, NHSO2, NHSO2NR17, NHCONH, OCONR19 or NR19COO, R15 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, (1-10C)haloalkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulf6nylamino(1-4C)alkyl, (N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy and R16, R17, R18 and R19 each independently represents hydrogen or (1-10C)alkyl, or R15 and R16, R17, R18 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and
R2 represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R3R4N in which R3 and R4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof.
According to another aspect, the present invention provides a method of potentiating glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof as defined herein.
According to another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof as defined herein for the manufacture of a medicament for potentiating glutamate receptor function.
According to yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as defined herein for potentiating glutamate receptor function.
It is understood that the following compounds of formula Ia and formula Ib are included within the scope of the present invention: 
More specifically, the following compounds of formula Ic and formula Id are further included within the scope of the present invention: 
wherein R2xe2x80x2 represents (1-4C)alkyl;
R30 represents hydrogen, F, Cl, Br, I, CN, CF3, NH2, NO2, CH3CONH, (1-4C) alkyl, (1-4C)alkoxy, and phenyl; and P is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
In addition, the following compounds of formula Ie and formula If are further included within the scope of the present invention: 
wherein R2xe2x80x2 represents (1-4C)alkyl; and
R31 represents hydrogen, F, Cl, Br, I, CN, CF3, NH2, (1-4C)alkyl, (1-4C)alkoxy), xe2x80x94(CH2)NHSO2R2xe2x80x3, xe2x80x94(CH2CH2)NHSO2R2xe2x80x3, xe2x80x94(CH2CH2CH2)NHSO2R2xe2x80x3, xe2x80x94(CH2)NHC(xe2x95x90O)Rxe2x80x3, xe2x80x94(CH2CH2)NHC(xe2x95x90O)Rxe2x80x3, xe2x80x94(CH2CH2CH2)NHC(xe2x95x90O)Rxe2x80x3, xe2x80x94(CH2)NHC(xe2x95x90O)ORxe2x80x3, xe2x80x94(CH2CH2)NHC(xe2x95x90O)ORxe2x80x3, xe2x80x94(CH2CH2CH2)NHC(xe2x95x90O)ORxe2x80x3, wherein R2xe2x80x3 represents CF3 or (1-4C)alkyl; or a pharmaceutically acceptable salt thereof.
In addition, the following compounds of formula Ig and formula Ih are included within the scope of the present invention: 
wherein R2xe2x80x2 represents (1-4C)alkyl; and
R31 represents hydrogen, F, Cl, Br, I, CN, CF3, NH2, (1-4C)alkyl, (1-4C)alkoxy), xe2x80x94(CH2)NHSO2R2xe2x80x3, xe2x80x94(CH2CH2)NHSO2R2xe2x80x3, xe2x80x94(CH2CH2CH2)NHSO2R2xe2x80x3, xe2x80x94(CH2)NHC(xe2x95x90O)Rxe2x80x3, xe2x80x94(CH2CH2)NHC(xe2x95x90O)Rxe2x80x3, xe2x80x94(CH2CH2CH2)NHC(xe2x95x90O)Rxe2x80x3, xe2x80x94(CH2)NHC(xe2x95x90O)ORxe2x80x3, xe2x80x94(CH2CH2)NHC(xe2x95x90O)ORxe2x80x3, xe2x80x94(CH2CH2CH2)NHC(xe2x95x90O)ORxe2x80x3, wherein R2xe2x80x3 represents CF3 or (1-4C)alkyl;
P is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
Preferred values for R2xe2x80x2 are methyl, ethyl and isopropyl, with isopropyl being most preferred.
Preferred values for R2xe2x80x3 are CF3, methyl, ethyl and isopropyl, with methyl being most preferred.
Preferred values for R30 are hydrogen, methyl, ethyl, isopropyl, Fl, Cl, CF3, CH3CONH and CN.
Preferred values for R31 are hydrogen, Fl, Cl, CN, methyl, ethyl, isopropyl, CF3, and xe2x80x94(CH2CH2)NHSO2R2xe2x80x3.
Preferred values for p are 0, 1 or 2.
It is understood that the compounds of formulas Ia, Ib, Ic, Id, Ie, If, Ig, and Ih, fall within the scope of the formula I.
In this specification, the term xe2x80x9cpotentiating glutamate receptor functionxe2x80x9d refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitisation or deactivation of AMPA receptors to glutamate.
A wide variety of conditions may be treated or prevented by the compounds of formula I and their pharmaceutically acceptable salts through their action as potentiators of glutamate receptor function. Such conditions include those associated with glutamate hypofunction, such as psychiatric and neurological disorders, for example cognitive disorders; neurodegenerative disorders such as Alzheimer""s disease; age-related dementias; age-induced memory impairment; movement disorders such as tardive dyskinesia, Hungtington""s chorea, myoclonus and Parkinson""s disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol-induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; and drug-induced psychosis. The compounds of formula I may also be useful for improving memory (both short term and long term) and learning ability. The present invention provides the use of compounds of formula I for the treatment of each of these conditions. In addition, the present invention provides the use of the compounds of formula I for treatment of sexual dysfunction.
The term xe2x80x9ctreatingxe2x80x9d (or xe2x80x9ctreatxe2x80x9d) as used herein includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom.
The present invention includes the pharmaceutically acceptable salts of the compounds defined by formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex3-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that the above salts may form hydrates or exist in a substantially anhydrous form.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                xc3x97                  E          2                                      E          1                +                  E          2                      xc3x97    100  
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. Examples of resolutions include recrystallization techniques or chiral chromatography.
Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
As used herein, the term xe2x80x9caromatic groupxe2x80x9d means the same as xe2x80x9carylxe2x80x9d, and includes phenyl and a polycyclic aromatic carbocyclic ring such as naphthyl.
The term xe2x80x9cheteroaromatic groupxe2x80x9d includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one to four atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl and quinolyl.
The term (1-10C)alkyl includes (1-8C)alkyl, (1-6C)alkyl and (1-4C)alkyl. Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
The term (2-10C)alkenyl includes (3-10C)alkenyl, (1-8C)alkenyl, (1-6C)alkenyl and (1-4C)alkenyl. Particular values are vinyl and prop-2-enyl.
The term (2-10C)alkynyl includes (3-10C)alkynyl, (1-8C)alkynyl, (1-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.
The term (1-10C)alkoxy includes (1-6C)alkoxy and further includes (1-4C)alkoxy. Particular values are methoxy, ethoxy, propoxy, butoxy, isopropoxy and isobutoxy.
The term (3-8C)cycloalkyl, as such or in the term (3-8C)cycloalkyloxy, includes monocyclic and polycyclic groups. Particular values are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[2.2.2]octane. The term includes (3-6C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term hydroxy(3-8C)cycloalkyl includes hydroxycyclopentyl, such as 3-hydroxycyclopentyl.
The term oxo(3-8C)cycloalkyl includes oxocyclopentyl, such as 3-oxocyclopentyl.
The term halogen includes fluorine, chlorine, bromine and iodine.
The term halo(1-10C)alkyl includes fluoro(1-10C)alkyl, such as trifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1-10C)alkyl such as chloromethyl.
The term cyano(2-10C)alkenyl includes 2-cyanoethenyl.
The term (2-4C)alkylene includes ethylene, propylene and butylene. A preferred value is ethylene.
The term thienyl includes thien-2-yl and thien-3-yl.
The term furyl includes fur-2-yl and fur-3-yl.
The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.
The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl.
The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and [1,2,4]oxadiazol-5-yl.
The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.
The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and [1,2,4]thiadiazol-5-yl.
The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl.
The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl and imidazolyl-5-yl.
The term triazolyl includes [1,2,4]triazol-3-yl and [1,2,4]triazol-5-yl.
The term tetrazolyl includes tetrazol-5-yl.
The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl and pyridazin-6-yl.
The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl.
The term benzofuryl includes benzofur-2-yl and benzofur-3-yl.
The term benzothienyl includes benzothien-2-yl and benzothien-3-yl.
The term benzimidazolyl includes benzimidazol-2-yl.
The term benzoxazolyl includes benzoxazol-2-yl.
The term benzothiazolyl includes benzothiazol-2-yl.
The term indolyl includes indol-2-yl and indol-3-yl.
The term quinolyl includes quinol-2-yl.
The term dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl, and the term (1-4C)alkoxycarbonyldihydrothiazolyl includes 4-methoxycarbonyl-4,5-dihydrothiazol-2-yl.
Examples of values for Ra and Rb are:
for Ra: F, CF3 and methoxy
for Rb: hydrogen, and
for Ra and Rb together xe2x95x90O and xe2x95x90CH2.
Examples of values for R2 are methyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino. Preferably R2 is ethyl, 2-propyl or dimethylamino.
Preferably R3 and R4 each represent methyl.
In the group of formula (CH2)yX1R9, examples of particular values for y are 0 and 1. X1 preferably represents O, CO, CONH or NHCO. R9 is preferably (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, pyrrolidinyl, morpholino or tetrahydrofuryl. Examples of values for R9are hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrrolidinyl, morpholino or 2-tetrahydrofuryl.
Particular values for the group (CH2)yX1R9 include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy, including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl, such as formyl and ethanoyl.
Preferably the group (CH2)yX1R9 represents CHO; COCH3, OCH3; OCH(CH3)2; NHCOR9 in which R9 represents methyl, ethyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrolidinyl or morpholino; CONHR9 in which R9 represents cyclopropyl or cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.
In the group of formula (CH2)zX3R15, examples of particular values for z are 0, 1, 2 and 3. z is preferably 0. X3 preferably represents O, CO, CONH or NHCO. Examples of values for R15 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.
Particular values for the group (CH2)zX3R15 include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C) alkynyloxy, including (3-6C) alkynyloxy, such as prop-2-ynyloxy; and (1-6C) alkanoyl, such as formyl and ethanoyl.
Preferably the group (CH2)zX3R15 represents NH2; CH2NH2; (CH2)2NH2; (CH2)3NH2; CONH2; CONHCH3; CON(CH3)2; N(C2H5)2; CH2OH; CH(OH)CH3; CH(OH)CH2CH3; CHO; COCH3; COOH; COOCH3; CH2NHCOOC(CH3)3; (CH2)2NHCOOC(CH3)3; NHSO2CH(CH3)2; a group of formula (CH2)2NHSO2R15 in which R15 represents CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH3)3CH3, benzyl, CH2CF3, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 1-(2-dimethylamino)naphthyl or 2-thienyl; CH(OH)CH2NHSO2CH3; (CH2)3NHSO2CH(CH3)2; COCH2N(OCOC(CH3)3)SO2CH3; COCH2NHSO2CH3; (CH2)2NHCOR15 in which R15 represents CH3, CH(CH3)2, CH2CH(CH3)2, phenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-thienyl, CHxe2x95x90CH, CHxe2x95x90CHCN, OCH3 or O(CH2)3CH3.
In the group of formula R14xe2x80x94(La)nxe2x80x94X2xe2x80x94(Lb)m, La and Lb preferably each independently represents CH2. X2 preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH or OCH2CONH. Examples of particular values for (La)nxe2x80x94X2-(Lb)m are a bond, O, NH, S, SO, SO2, CO, CH2, COCH2, COCONH, CH(OH)CH2, CONH, NHCO, NHCONH, CH2O, OCH2, OCH2CONH, CH2NH, NHCH2 and CH2CH2.
R14 is preferably an unsubstituted or substituted phenyl, naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidyl benzothienyl or benzothiazolyl group.
Examples of particular values for R14 are phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl, 2-prop-2-enylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-bromomethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-hydroxyphenyl, 2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl, 2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-butoxyphenyl, 2-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl, 3-(1-hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl, 2-(1-hydroxypropyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-(1-hydroxy-2,2-dimethyl-propyl)phenyl, 4-trifluoromethoxyphenyl, 2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3-aminopropyl)phenyl, 4-carboxyphenyl, 4-carbamoylphenyl, 4-N-methylcarbamoylphenyl, 4-N,N-dimethylcarbamoylphenyl, 2-isopropylaminomethylphenyl, 4-t-butoxycarbonylaminomethylphenyl, 4-(2-isopropoxycarboxamido)ethylphenyl, 4-(2-t-butoxycarboxamido)ethylphenyl, 4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonylamino)ethylphenyl, 4-(2-ethylsulfonylamino)ethylphenyl, 4-(3-isopropylsulfonylamino)propylphenyl, 4-(1-(2-(2-propane)sulfonylamino)propyl)phenyl, 4-(2-propylsulfonylamino)ethylphenyl, 4-(2-isopropylsulfonylamino)ethylphenyl, 4-(2-butylsulfonylamino)ethylphenyl, 4-(1-isopropylsulfonylaminomethyl)ethylphenyl, 4-(1-hydroxy-2-methanesulfonylamino)ethylphenyl, 4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonylamino)ethylphenyl, 4-(2-(2,2,2-trifluoroethyl)sulfonylamino)ethylphenyl, 4-(2-N,N-dimethylaminosulfonylamino)ethylphenyl, 4-(2-phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl, 4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)phenyl, 4-(2-(4-fluorobenzamido)ethyl)phenyl, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3-fluorobenzamido)ethyl)phenyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2-methoxybenzamido)ethyl)phenyl, 4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl, 4-(1-(2-(10-amphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonylmino)ethyl)phenyl, 4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl, 4-(N-(t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl, 4-(2-(2-thienylcarboxamido)ethyl)phenyl, thien-2-yl, 5-hydroxymethylthien-2-yl, 5-formylthien-2-yl, thien-3-yl, 5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2-bromothien-3-yl, fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl, 3-bromoisoxazol-5-yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl, 5-methylisoxazol-3-yl, 5-hydroxymethylisoxazol-3-yl, 5-methyl-3-phenylisoxazol-4-yl, 5-(2-hydroxyethyl)isoxazol-3-yl, 5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl, 5-N-methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl, 3-bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl, 4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl, 4-carboxythiazol-2-yl, imidazol-1-yl, 2-sulfhydrylimidazol-1-yl, [1,2,4]triazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 2-ethyltetrazol-5-yl, 2-isopropyltetrazol-5-yl, 2-(2-propenyl)tetrazol-5-yl, 2-benzyltetrazol-5-yl, pyrid-2-yl, 5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl, 5-trifluoromethylpyrid-2-yl, 6-chloropyridazin-3-yl, 6-methylpyridazin-3-yl, 6-methoxypyrazin-3-yl, pyrimidin-5-yl, benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl.
Examples of an unsubstituted or substituted aromatic or heteroaromatic group represented by R1 are unsubstituted or substituted phenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl.
Preferably, R1 represents 2-naphthyl or a group of formula 
in which
R20 represents halogen; nitro; cyano; hydroxyimino; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl; (CH2)yX1R9 in which y is 0 or an integer of from 1 to 4, X1 represents O, S, NR10, CO, COO, OCO, CONR11, NR12CO, NR12COCOO, OCONR13, R9 represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10, R11, R12 and R13 each independently represents hydrogen or (1-10C)alkyl, or R9 and R10, R11, R12 or R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C) alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl; (1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; benzothiazolyl; and a group of formula R14xe2x80x94(La)nxe2x80x94X2xe2x80x94(Lb)m in which X2 represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH, OCH2CONH or CHxe2x95x90CH, NHCO, La and Lb each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl); halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; (CH2)zX3R15 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH(OH), COO, OCO, CONR17, NR18CO, NHSO2, NHSO2NR17, NHCONH, OCONR19 or NR19COO, R15 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, (1-10C)haloalkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, (1-4C)haloalkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R16, R17, R18 and R19 each independently represents hydrogen or (1-10C)alkyl, or R15 and R16, R17, R18 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and
R21 represents a hydrogen atom, a halogen atom, a (1-4C)alkyl group or a (1-4C)alkoxy group.
Examples of particular values for R20 are fluorine, chlorine, bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopentyl, cyclohexyl, 3-hydroxycyclopentyl, 3-oxocyclopentyl, methoxy, ethoxy, propoxy, 2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido, 1-butanoylamido, t-butylcarboxamido, acryloylamido, 2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy, morpholinocarboxamido, methyloxalylamido, cyclopropylcarboxamido, cyclobutylcarboxamido, cyclopentylcarboxamido, cyclohexylcarboxamido, cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino, piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2-yl, 4,5-dihydro-4-methoxycarbonyl-5,5-dimethylthiazol-2-yl, benzothien-2-yl, benzothiazol-2-yl, phenyl, 4-hydroxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,3-difluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 2-methylphenyl, 4-methylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl, 3-trifluoromethylphenyl, 4-trifluoro-methylphenyl, 4-(2-cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 3-acetylphenyl, 4-acetylphenyl, 4-carboxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxymethylphenyl, 4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl, 4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3-aminopropyl)phenyl, 4-(2-acetylaminoethyl)phenyl, 4-t-butoxycarboxylaminoethyl)phenyl, 4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino, 4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonylaminoethyl)phenyl, 4-(2-ethylsulfonylaminoethyl)phenyl, 4-(2-propylsulfonylaminoethyl)phenyl, 4-(2-butylsulfonylaminoethyl)phenyl, 4-(2-isopropylsulfonylaminoethyl)phenyl, 4-(1-hydroxy-2-methanesulfonylaminoethyl)phenyl, 4-(2-dimethylaminosulfonylaminoethyl)phenyl, 4-(1-(2-(2-propyl)sulfonylaminopropyl)phenyl, 4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonylaminoethyl)phenyl, 4-(2-phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl, 4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)phenyl, 4-(2-(4-fluorobenzamido)ethyl)phenyl, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3-fluorobenzamido)ethyl)phenyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2-methoxybenzamido)ethyl)phenyl, 4-(2-(2-thienylcarboxamido)ethyl)phenyl, 4-carbamoylphenyl, 4-methylcarbamoylphenyl, 4-dimethylcarbamoylphenyl, 4-(2-(2-methylpropaneamido)ethyl)phenyl, 4-(2-(3-methylbutaneamido)ethyl)phenyl, benzoylmethyl, benzamido, 2-fluorobenzamido, 3-flurobenzamido, 4-fluorobenzamido, 2,4-difluorobenzamido, 3-chlorobenzamido, 4-chlorobenzamido, 4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3-methylbenzamido, 4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido, 4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido, 3-trifluoromethylbenzamido, 4-trifluoromethylbenzamido, 2-fluoro-4-trifluoromethylbenzamido, 2-methoxybenzamido, 3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido, 4-phenylphenylcarboxamido, 4-benzylcarboxamido, 4-phenoxymethylcarboxamido, 2-fluorobenzylamino, benzyloxy, 2-fluorobenzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl, 4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl, 4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonylamino)ethyl)phenyl, 4-(2-phenylacetamido)ethyl)phenyl, 4-(methanesulfonylaminoethanoyl)phenyl, 4-(N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl, 2-thienylcarboxamido, 2-furylcarboxamido, 3-(5-methylisoxazolyl)carboxamido, 5-isoxazolylcarboxamido, 2-benzothienylcarboxamido, 4-(5-methyl-3-phenylisoxazolyl)carboxamido, 4-pyridylcarboxamido, 2-(5-nitrofuryl)carboxamido, 2-pyridylcarboxamido, 6-chlord-2-pyridylcarboxamido, 2-thienylsulfonamido, 2-thienylmethylamino, 3-thienylmethylamino, 2-furylmethylamino, 3-furylmethylamino, 3-acetylureido and 2-(2-thienyl)ethylureido.
Examples of particular values for R21 are hydrogen and chlorine. R21 is preferably ortho to R20.
Examples of particular values for R1 are 2-naphthyl, 4-bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropylphenyl, 4-isobutylphenyl, 4-t-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)phenyl, 4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)phenyl, 4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 3-chloro-4-piperidin-1-ylphenyl, 4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)phenyl, 4-(4-formylphenyl)phenyl, 4-(4-methylphenyl)phenyl, 4-(4-hydroxphenyl)phenyl, 4-(2-methoxyphenyl)phenyl and 4-(4-methoxyphenyl)phenyl.
The compounds of formula I may be prepared as described below. The reagents and starting material are readily available to one of ordinary skill in the art, for example see International Patent Application Publication WO 98/33496. Thus, the compounds of formula I may be prepared by:
(a) reacting a compound of formula 
with a compound of formula
R2SO2Z1xe2x80x83xe2x80x83III
in which Z1 represents a leaving atom or group; or
(b) for a compound of formula I in which Ra and Rb together represent xe2x95x90O, reacting a compound of formula 
in which Z2 represents a leaving atom or group, with a compound of formula
HNRxSO2R2xe2x80x83xe2x80x83V
in which Rx represents a hydrogen atom or an amine protecting group; followed where necessary and/or desired by removing any amine protecting group and forming a pharmaceutically acceptable salt.
In process step (a), the leaving atom or group represented by Z1 may be, for example, a halogen atom such as a chlorine or bromine atom. The reaction is conveniently performed in the presence of a base, for example an alkali metal hydroxide such as sodium hydroxide, an alkali metal carbonate such as potassium carbonate, a tertiary amine such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene. Suitable solvents include halogenated hydrocarbons such as dichloromethane. The reaction is conveniently performed at a temperature in the range of from xe2x88x9220 to 100xc2x0 C., preferably from xe2x88x925 to 50xc2x0 C.
In process step (b), the amine protecting group represented by Rx may be a conventional amine protecting group. The protection of amine groups is generally described in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973, and Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd. Ed., John Wiley and Sons, NY, 1991. Examples of amine protecting groups include acyl groups, such as groups of formula RyCO in which Ry represents (1-6C) alkyl, (3-10C) cycloalkyl, phenyl(1-6C) alkyl, phenyl, (1-6C) alkoxy, phenyl(1-6C)alkoxy, or a (3-10C) cycloalkoxy, wherein a phenyl group may optionally be substituted by one or two substituents independently selected from amino, hydroxy, nitro, halogeno, (1-6C) alkyl, (1-6C) alkoxy, carboxy, (1-6C) alkoxycarbonyl, carbamoyl, (1-6C) alkanoylamino, (1-6C) alkylsulphonylamino, phenylsulphonylamino, toluenesulphonylamino, and (1-6C)fluoroalkyl. An example of a preferred amine protecting group is t-butoxycarbonyl. It may be removed by hydrolysis, for example using trifluoroacetic acid.
The leaving atom or group represented by Z2 may be, for example, a halogen atom such as a chlorine or bromine atom. The reaction is conveniently performed in the presence of a base, for example an alkali metal hydroxide such as sodium hydroxide, an alkali metal carbonate such as potassium carbonate, a tertiary amine such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene. Suitable solvents include halogenated hydrocarbons such as dichloromethane, nitriles, such as acetonitrile and ethers such as tetrahydrofuran. The reaction is conveniently performed at a temperature in the range of from xe2x88x9220 to 100xc2x0 C., preferably from xe2x88x925 to 50xc2x0 C.
The compounds of formula I in which R1 represents a 4-bromophenyl group may conveniently be converted into other compounds of formula I in which R represents another 4-substituted phenyl group by reaction with an appropriate boronic acid derivative, for example, 3-thiopheneboronic acid. The reaction is conveniently performed in the presence of a tetrakis (triarylphosphine)palladium(0) catalyst, such as tetrakis (triphenylphosphine)palladium(0) and a base such as potassium carbonate. Convenient solvents for the reaction include aromatic hydrocarbons, such as toluene, and ethers, such as dioxane. The temperature at which the reaction is conducted is conveniently in the range of from 0 to 150xc2x0 C., preferably 75 to 120xc2x0 C. Bis aromatic intermediates useful in the preparation of compounds of formula I may be prepared by reacting a bromoaromatic or bromoheteroaromatic compound with an aromatic or heteroaromatic boronic acid in an analogous manner.
The boronic acid derivative used as a starting material may be prepared by reacting a trialkyl borate, such as triisopropyl borate with an appropriate organolithium compound at reduced temperature. For example, 2-fluorobenzeneboronic acid may be prepared by reacting 2-fluorobromobenzene with butyllithium in tetrahydrofuran at about xe2x88x9278xc2x0 C. to afford 2-fluorophenyl lithium, and then reacting this organolithium compound with triisopropyl borate.
Alternatively, the compounds of formula I in which R1 represents a 4-bromophenyl group may be converted to a 4-(trimethylstannyl)phenyl or 4-(tri-n-butylstannyl)phenyl group by treatment of the corresponding bromide with a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and hexaalkyldistannane, where the alkyl group is methyl or n-butyl, in an aprotic solvent such as toluene in the presence of a tertiary amine base such as triethylamine, at temperatures ranging from 80 to 140xc2x0 C., preferably from 90 to 110xc2x0 C.
The compounds of formula I in which R1 represents a 4-(tri-n-butylstannyl)phenyl group may then be reacted with an aryl- or heteroarylbromide, such as 2-bromothiophene-5-carboxaldehyde, in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0), or a palladium(II) catalyst, such as bis(triphenylphosphine)palladium(II) dichloride, in an aprotic solvent, such as dioxane, at temperatures ranging from 80 to 140xc2x0 C., preferably from 90 to 110xc2x0 C., to afford the corresponding 4-(aryl)phenyl or 4-(heteroaryl)phenyl substituted compound.
The compounds of formula I in which R1 represents a 4-bromophenyl group may be converted into other compounds of formula I in which R1 represents a 4-substituted alkyl- or cycloalkylphenyl group, such as 4-cyclopentylphenyl by treatment of the corresponding bromide with an appropriate alkyl- or cycloalkyl Grignard reagent, such as cyclopentylmagnesium bromide, in the presence of a palladium(II) catalyst, such as [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)), in an aprotic solvent, such as diethyl ether at temperatures ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C.
The compounds of formula I in which R1 represents a 4-bromophenyl group may be converted into a 4-substituted carboxyaldehydephenyl(formylphenyl) group by reaction of the corresponding bromide with the carbon monoxide gas which is bubbled into the reaction under atmospheric pressure in the presence of a palladium(II) catalyst, such as bis(triphenylphosphine)palladium(II) dichloride and sodium formate in an aprotic solvent, such as dimethylformamide at temperatures ranging from 70 to 110xc2x0 C., preferably at 90xc2x0 C.
The compounds of formula I in which R1 represents a 4-hydroxyphenyl group may be converted into other compounds of formula I in which R1 represents an alkoxy group by treatment of the corresponding hydroxyphenyl group with an appropriate alkylhalide such as benzylbromide in the presence of sodium hydride in an aprotic solvent such as dimethylformamide at temperatures ranging from 25 to 100xc2x0 C., preferably from 50 to 90xc2x0 C. The compounds of formula I in which Ra and Rb together represent xe2x95x90O may be converted into a compound of formula I in which one of Ra and Rb represents ORc and the other represents hydrogen by reduction, for example using lithium aluminium hydride or sodium borohydride, to afford a compound of formula I in which one of Ra and Rb represents OH, followed if desired by alkylation, for example by reaction with a (1-4C)alkyl halide in the presence of a base to afford a compound of formula I in which Ra represents (1-4C)alkoxy.
The compounds of formula I in which Ra and Rb together represent xe2x95x90O may be converted into a compound of formula I in which Ra and Rb together represent xe2x95x90CH2 by a Wittig reaction.
The compounds of formula I in which Ra and Rb together represent xe2x95x90O may be converted into a compound of formula I in which Ra and Rb each represents fluorine by reaction with a fluorinating agent such as diethylaminosulfur trifluoride or dimethylaminosulfur trifluoride, according to the method described in J. Org. Chem, 50, 1599, 1985 and Tet. Lett., 34(31), 4917, 1993. The reaction is conveniently performed in a solvent such as dichloromethane or tetrahydrofuran at a temperature in the range of from 0 to 50xc2x0 C. Alternative fluorinating agents are hydrogen fluoride in trifluoroacetic acid and CF2Br2 with zinc dust (J. Chem. Soc. Perk. Trans. 1, 3, 335, 1993). Alternatively, the compound of formula I may be converted to a dithiolane by reaction with H2SCH2CH2SH, followed by reaction with BF3-acetic acid complex (J. Org. Chem., 51, 3508, 1986).
The compounds of formula II are known or may be prepared by conventional methods, for example by reducing a corresponding amide or nitrile using a borane.
Alternatively, the compounds of formula II in which Ra represents CF3 may be prepared by reducing a compound of formula 
for example by catalytic hydrogenation using a Group VIII metal catalyst, such as palladium on charcoal.
The compounds of formula VI may be prepared by reacting a compound of formula 
with nitromethane. The reaction is conveniently performed in the presence of a base, such as diethylenediamine in a solvent, such as toluene, and using a Dean and Stark trap to remove water formed during the reaction.
The compounds of formula IV are known or may be prepared by conventional methods. For example a compound of formula IV in which Z1 represents a bromine atom may be prepared from the corresponding ketone of formula 
by bromination using an electrophilic brominating agent, such as bromine or N-bromosuccinimide. Convenient solvents include acetic acid. Alternatively, they may be prepared by treating the corresponding ketone of formula VIII with a strong base, such as lithium diisopropyl amide or lithium bis(trimethylsilyl)amide in a solvent such as tetrahydrofuran, followed by a brominating agent, such as bromine or N-bromosuccinimide.
More specifically, compounds of formula Ia and formula Ib can be prepared following generally the procedure described in Scheme I. The reagents and starting materials are readily available to one of ordinary skill in the art. Unless otherwise indicated, the substituents are defined as above. 
In Scheme I, step A the nitrile of structure (1) is fluorinated to provide the monofluoro compound (2a) and the difluoro compound (2b). For example, the nitrile (1) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran and about 2.2 equivalents of N-fluorobenzene sulfonamide is added to the solution under an atmosphere of nitrogen. The solution is cooled to about xe2x88x9278xc2x0 C. with stirring and treated dropwise with about 2.2 equivalents of lithium-bis-(trimethylsilyl)amide. The reaction is then allowed to warm to room temperature and then stirred for about 8 to 16 hours. The reaction mixture is then diluted with water and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude mixture of compounds (2a) and (2b). These are separated and purified by techniques well known in the art, such as flash or radial (Chromatotron, Harrison Research Inc., Palo Alto, Calif.) chromatography on silica gel. For example, the crude material is purified by radial chromaography on a 4000 micron silica gel rotor eluting with a suitable eluent, such as ethyl acetate/hexane to provide separately the purified monofluoro compound (2a) and the difluoro compound (2b).
In Scheme I, step B each compound (2a) and (2b) can be reduced under standard conditions well known in the art to provide the amino derivatives (3a) and (3b). For example, either compound (3a) or compound (3b) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran at room temperature under an atmosphere of nitrogen wit stirring. The solution is then treated with about 1.3 equivalents of BH3-THF complex and stirred for about 4 to 24 hours. The reaction mixture is then treated with an excess of a mixture of THF/methanol (1:1) followed by dropwise addition of excess 5.0 N sodium hydroxide. The reaction mixture is then stirred under reflux for about 3 to 6 hours and then cooled to room temperature. The reaction mixture is then diluted with a suitable organic solvent, such as ethyl acetate. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude material. The crude material is purified by standard techniques well known in the art such as flash or radial chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride to provide the purified compounds (3a) or (3b).
In Scheme I, step C the compounds (3a) or (3b) are converted to the corresponding sulfonamides of formula (Ia) or formula (Ib) under conditions well known in the art. For example, either compound (3a) or (3b) is dissolved in a suitable organic solvent, such as dry methylene chloride under an atmosphere of nitrogen. To this solution is added about 2.1 equivalents of DBU. The solution is then cooled to about 0xc2x0 C. and treated dropwise with about 1.1 equivalents of a compound of formula ClSO2R2. The reaction mixture is then allowed to warm to room temperature and stirred for about 8 to 16 hours. It is then poured into water and the organic layer is separated. The organic layer is then washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude product of formula (Ia) or formula (Ib). This crude material can then be purified by standard techniques well known in the art, such as flash or radial chromatography bn silica gel with a suitable eluent, such as hexane/ethyl acetate to provide the purified compounds of formula (Ia) or formula (Ib).
The ability of compounds of formula I to potentiate glutamate receptor-mediated response may be determined using fluorescent calcium indicator dyes (Molecular Probes, Eugene, Oreg., Fluo-3) and by measuring glutamate-evoked efflux of calcium into GluR4 transfected HEK293 cells, as described in more detail below.
In one test, 96 well plates containing confluent monolayers of HEK cells stably expressing human GluR4B (obtained as described in European Patent Application Publication Number EP-A1-583917) are prepared. The tissue culture medium in the wells is then discarded, and the wells are each washed once with 200 xcexcl of buffer (glucose, 10 mM, sodium chloride, 138 mM, magnesium chloride, 1 mM, potassium chloride, 5 mM, calcium chloride, 5 mM, N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], 10 mM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutes in the dark with 20 xcexcM Fluo3-AM dye (obtained from Molecular Probes Inc, Eugene, Oreg.) in buffer in each well. After the incubation, each well is washed once with 100 xcexcl buffer, 200 xcexcl of buffer is added and the plates are incubated for 30 minutes.
Solutions for use in the test are also prepared as follows. 30 xcexcM, 10 xcexcM, 3 xcexcM and 1 xcexcM dilutions of test compound are prepared using buffer from a 10 mM solution of test compound in DMSO. 100 xcexcM cyclothiazide solution is prepared by adding 3 xcexcl of 100 mM cyclothiazide to 3 ml of buffer. Control buffer solution is prepared by adding, 1.5 xcexcl DMSO to 498.5 xcexcl of buffer.
Each test is then performed as follows. 200 xcexcl of control buffer in each well is discarded and replaced with 45 xcexcl of control buffer solution. A baseline fluorescent measurement is taken using a FLUOROSKAN II fluorimeter (Obtained from Labsystems, Needham Heights, Mass., USA, a Division of Life Sciences International Plc). The buffer is then removed and replaced with 45 xcexcl of buffer and 45 xcexcl of test compound in buffer in appropriate wells. A second fluorescent reading is taken after 5 minutes incubation. 15 xcexcl of 400 xcexcM glutamate solution is then added to each well (final glutamate concentration 100 xcexcM), and a third reading is taken. The activities of test compounds and cyclothiazide solutions are determined by subtracting the second from the third reading (fluorescence due to addition of glutamate in the presence or absence of test compound or cyclothiazide) and are expressed relative to enhance fluorescence produced by 100 xcexcM cyclothiazide.
In another test, HEK293 cells stably expressing human GluR4 (obtained as described in European Patent Application Publication No. EP-A1-0583917) are used in the electrophysiological characterization of AMPA receptor potentiators. The extracellular recording solution contains (in mM): 140 NaCl, 5 KCl, 10 HEPES, 1 MgCl2, 2 CaCl2, 10 glucose, pH=7.4 with NaOH, 295 mOsm kgxe2x88x921. The intracellular recording solution contains (in mM): 140 CsCl, 1 MgCl2, 10 HEPES, (N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA (ethylene-bis(oxyethylenenitrilo)tetraacetic acid), pH=7.2 with CsOH, 295 mOsm kgxe2x88x921. With these solutions, recording pipettes have a resistance of 2-3 Mxcexa9. Using the whole-cell voltage clamp technique (Hamill et al. (1981) Pflxc3xcgers Arch., 391: 85-100), cells are voltage-clamped at xe2x88x9260 mV and control current responses to 1 mM glutamate are evoked. Responses to 1 mM glutamate are then determined in the presence of test compound. Compounds are deemed active in this test if, at a test concentration of 10 xcexcM, they produce a greater than 30% increase in the value of the current evoked by 1 mM glutamate.
In order to determine the potency of test compounds, the concentration of the test compound, both in the bathing solution and co-applied with glutamate, is increased in half log units until the maximum effect was seen. Data collected in this manner are fit to the Hill equation, yielding an EC50 value, indicative of the potency of the test compound. Reversibility of test compound activity is determined by assessing control glutamate 1 mM responses. Once the control responses to the glutamate challenge are re-established, the potentiation of these responses by 100 xcexcM cyclothiazide is determined by its inclusion in both the bathing solution and the glutamate-containing solution. In this manner, the efficacy of the test compound relative to that of cyclothiazide can be determined.
According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove and a pharmaceutically acceptable diluent or carrier.
The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
As used herein the term xe2x80x9cpatientxe2x80x9d refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
As used herein the term xe2x80x9ceffective amountxe2x80x9d refers to the amount or dose of the compound which provides the desired effect in the patient under diagnosis or treatment.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300 mg (for example 25 mg) of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
Hard gelatin capsules are prepared using the following ingredients:
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
Tablets each containing 60 mg of active ingredient are made as follows:
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
The particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.